A range of different approaches have been used for modifying the structure of glucagon-like peptide 1 (GLP-1) compounds in order to provide a longer duration of action in vivo.
WO 2006/097538, WO 2006/097536, WO 2006/037810, WO2006005667, WO 2005/027978. WO 98/08871 and US 2001/0011071 describes various GLP-1 analogues and derivatives thereof.
Runge et al (Journal of Biological Chemistry, vol. 283, no. 17, pp. 11340-11347), which was published after the priority dates of the present invention, discloses the crystal structure of the extracellular domain of the ligand-bound GLP-1 receptor.
Many diabetes patients particularly in the type 2 diabetes segment are subject to so-called “needle-phobia”, i.e. a substantial fear of injecting themselves. In the type 2 diabetes segment most patients are treated with oral hypoglycaemic agents, and since GLP-1 compounds are expected to be an injectable pharmaceutical product these patients will be administered, the fear of injections may become a serious obstacle for the widespread use of the clinically very promising compounds. Thus, there is a need to develop new compounds which can be administered less than once daily, e.g. once every second or third day preferably once weekly, while retaining an acceptable clinical profile or optionally via non invasive administration such as pulmonary, nasal, sublingual, buccal or oral administration.
One object of the present invention is to provide a chemically, physically and enzymatically stable GLP-1 analogue or derivative thereof.
A further object of the invention is to provide a long acting, i.e. having an administration regimen as described above, GLP-1 analogue or derivative thereof.
Another object of this invention is to provide a GLP-1 analogue or derivative thereof with high potency (receptor affinity) in order to reduce the therapeutic dose used for example for once weekly s.c. dosing or alternatively for non-invasive delivery.
Another object of this invention is to provide a GLP-1 compound with a high binding affinity to the GLP-1 receptor (GLP-1R).
A still further object of this invention is to provide a GLP-1 compound with a high binding affinity to the extracellular domain of the GLP-1 receptor (nGLP-1R).
Another object of this invention is to provide a GLP-1 analogue or derivative thereof with high albumin binding affinity which protects the peptide for proteolytic degradation and reduce renal clearance of the peptide.
Potency, binding affinity to the GLP-1 receptor, and possibly also to the extracellular domain of the GLP-1 receptor are properties of potential relevance for an overall object of achieving long-acting, stable and of course therapeutically active GLP-1 derivatives with a potential for once weekly administration.